| 1. |
- Campbell, PJ, et al.
(författare)
-
Pan-cancer analysis of whole genomes
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
|
|
| 2. |
|
|
| 3. |
- Lee, H. J., et al.
(författare)
-
Efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy for advanced EGFR-mutated non-small cell lung cancer: systematic review and meta-analysis
- 2021
-
Ingår i: European Review for Medical and Pharmacological Sciences. - : VERDUCI PUBLISHER. - 1128-3602 .- 2284-0729. ; 25:20, s. 6232-6244
-
Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: It is controversial whether there is efficacy or safety benefit of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced EGFR-mutated non small cell lung cancer (NSCLC) compared to standard chemotherapy. We aim to assess the efficacy and safety of EGFR-TKIs compared to another chemotherapeutics in EGFR-mutated NSCLC. MATERIALS AND METHODS: Up to April 27th, 2020, PubMed, Embase, Medline, Scopus, Cochrane library, and ClinicalTrials.gov were searched for articles or trials meeting the inclusion criteria. After filtering, 230 eligible studies were initially identified. Data extraction followed PRISMA and included outcomes were progression-free survival (PFS), overall survival (OS), and severe adverse events (SAEs). Direct and indirect meta-analyses were generated in the context of log-linear mixed-effects models, with fixed effects for each relative comparison and random effects for each study. RESULTS: The results showed that EGFR-TKI therapy had improved PFS with a hazard ratio (HR) of 0.40 (95% CI: 0.36-0.44, p<0.001) compared to standard chemotherapy. Nevertheless, the EGFR-TKIs showed no benefit on OS (HR: 0.96, 95% CI: 0.83-1.10, p=0.556). In the analysis of adverse events, EGFR-TKIs had fewer SAEs than standard chemotherapy (HR: 0.29, 95% CI: 0.26-0.33, p<0.001). CONCLUSIONS: Our systemic review indicates that EGFR-TKI therapy has improved PFS, and reduced SAEs compared to standard chemotherapy in advanced EGFR-mutated NSCLC.
|
|
| 4. |
- Douglas, T. A., et al.
(författare)
-
The use of hydrogel microparticles to sequester and concentrate bacterial antigens in a urine test for Lyme disease
- 2011
-
Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 32:4, s. 1157-1166
-
Tidskriftsartikel (refereegranskat)abstract
- Hydrogel biomarker capturing microparticles were evaluated as a biomaterial to amplify the sensitivity of urine testing for infectious disease proteins. Lyme disease is a bacterial infection transmitted by ticks. Early diagnosis and prompt treatment of Lyme disease reduces complications including arthritis and cardiac involvement. While a urine test is highly desirable for Lyme disease screening, this has been difficult to accomplish because the antigen is present at extremely low concentrations, below the detection limit of clinical immunoassays. N-isopropylacrylamide (NIPAm) - acrylic acid (AAc) microparticles were covalently functionalized with amine containing dyes via arnidation of carboxylic groups present in the microparticles. The dyes act as affinity baits towards protein analytes in solution. NIPAm/AAc microparticles functionalized with acid black 48 (AB48) mixed with human urine, achieved close to one hundred percent capture and 100 percent extraction yield of the target antigen. In urine, microparticles sequestered and concentrated Lyme disease antigens 100 fold, compared to the absence of microparticles, achieving an immunoassay detection sensitivity of 700 pg/mL in 10 mL urine. Antigen present in a single infected tick could be readily detected following microparticle sequestration. Hydrogel microparticles functionalized with high affinity baits can dramatically increase the sensitivity of urinary antigen tests for infectious diseases such as Lyme disease. These findings justify controlled clinical studies evaluating the sensitivity and precision of Lyme antigen testing in urine.
|
|
| 5. |
- Meani, F, et al.
(författare)
-
Investigation of the Ovarian and Prostate Cancer Peptidome for Candidate Early Detection Markers Using a Novel Nanoparticle Biomarker Capture Technology
- 2010
-
Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 2:4, s. 504-518
-
Tidskriftsartikel (refereegranskat)abstract
- Current efforts to identify protein biomarkers of disease use mainly mass spectrometry (MS) to analyze tissue and blood specimens. The low-molecular-weight "peptidome" is an attractive information archive because of the facile nature by which the low-molecular-weight information freely crosses the endothelial cell barrier of the vasculature, which provides opportunity to measure disease microenvironment-associated protein analytes secreted or shed into the extracellular interstitium and from there into the circulation. However, identifying useful protein biomarkers (peptidomic or not) which could be useful to detect early detection/monitoring of disease, toxicity, doping, or drug abuse has been severely hampered because even the most sophisticated, high-resolution MS technologies have lower sensitivities than those of the immunoassays technologies now routinely used in clinical practice. Identification of novel low abundance biomarkers that are indicative of early-stage events that likely exist in the sub-nanogram per milliliter concentration range of known markers, such as prostate-specific antigen, cannot be readily detected by current MS technologies. We have developed a new nanoparticle technology that can, in one step, capture, concentrate, and separate the peptidome from high-abundance blood proteins. Herein, we describe an initial pilot study whereby the peptidome content of ovarian and prostate cancer patients is investigated with this method. Differentially abundant candidate peptidome biomarkers that appear to be specific for early-stage ovarian and prostate cancer have been identified and reveal the potential utility for this new methodology
|
|
| 6. |
- Fredolino, C, et al.
(författare)
-
Nanoparticles technology : Amplifying the effective sensitivity of biomarker detection to create a urine test for hGH
- 2009
-
Ingår i: Drug Test Analysis. - 1942-7611. ; 1:9-10, s. 447-454
-
Tidskriftsartikel (refereegranskat)abstract
- Several clinical-grade immunoassays exist for the specific measurement of hGH or its isoforms in blood but there is an urgent need to apply these same reliable assays to the measurement of hGH in urine as a preferred 'non-invasive' biofluid. Unfortunately, conventional hGH immunoassays cannot attain the sensitivity required to detect the low concentrations of hGH in urine. The lowest limit of sensitivity for existing hGH immunoassays is >50 pg/mL, while the estimated concentration of urinary hGH is about 1 pg/m-50 times lower than the sensitivity threshold. We have created novel N-isopropylacrylamide (NIPAm)-based hydrogel nanoparticles functionalized with an affinity bait. When introduced into an analyte-containing solution, the nanoparticles can perform, in one step, (1) complete harvesting of all solution phase target analytes, (2) full protection of the captured analyte from degradation and (3) sequestration of the analyte, effectively increasing the analyte concentration up to a hundredfold. N-isopropylacrylamide nanoparticles functionalized with Cibacron Blue F3GA bait have been applied to raise the concentration of urinary hGH into the linear range of clinical grade immunoassays. This technology now provides an opportunity to evaluate the concentration of hGH in urine with high precision and accuracy
|
|
| 7. |
- Tamburro, Davide, et al.
(författare)
-
Multifunctional Core-Shell Nanoparticles : Discovery of Previously Invisible Biomarkers
- 2011
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:47, s. 19178-19188
-
Tidskriftsartikel (refereegranskat)abstract
- Many low-abundance biomarkers for early detection of cancer and other diseases are invisible to mass spectrometry because they exist in body fluids in very low concentrations, are masked by high-abundance proteins such as albumin and immunoglobulins, and are very labile. To overcome these barriers, we created porous, buoyant, core-shell hydrogel nanoparticles containing novel high affinity reactive chemical baits for protein and peptide harvesting, concentration, and preservation in body fluids. Poly(N-isopropylacrylamide-co-acrylic acid) nanoparticles were functionalized with amino-containing dyes via zero-length cross-linking amidation reactions. Nanoparticles functionalized in the core with 17 different (12 chemically novel) molecular baits showed preferential high affinities (K(D) < 10(-11) M) for specific low-abundance protein analytes. A poly(N-isopropylacrylamide-co-vinylsulfonic acid) shell was added to the core particles. This shell chemistry selectively prevented unwanted entry of all size peptides derived from albumin without hindering the penetration of non-albumin small proteins and peptides. Proteins and peptides entered the core to be captured with high affinity by baits immobilized in the core. Nanoparticles effectively protected interleukin-6 from enzymatic degradation in sweat and increased the effective detection sensitivity of human growth hormone in human urine using multiple reaction monitoring analysis. Used in whole blood as a one-step, in-solution preprocessing step, the nanoparticles greatly enriched the concentration of low-molecular weight proteins and peptides while excluding albumin and other proteins above 30 kDa; this achieved a 10,000-fold effective amplification of the analyte concentration, enabling mass spectrometry (MS) discovery of candidate biomarkers that were previously undetectable.
|
|
| 8. |
- Luchini, Alessandra, et al.
(författare)
-
The impact of deuteration on natural and synthetic lipids : A neutron diffraction study
- 2018
-
Ingår i: Colloids and Surfaces B: Biointerfaces. - : Elsevier BV. - 0927-7765. ; 168, s. 126-133
-
Tidskriftsartikel (refereegranskat)abstract
- The structural investigation of cellular membranes requires access to model systems where the molecular complexity is representative of the cellular environment and that allow for the exploitation of structural techniques. Neutron scattering, and in particular neutron diffraction can provide unique and detailed information on the structure of lipid membranes. However, deuterated samples are desirable to fully exploit this powerful method. Recently, the extraction of lipids from microorganisms grown in deuterated media was demonstrated to be both an attracting route to obtain complex lipid mixtures resembling the composition of natural membranes, and to producing deuterated molecules in a very convenient way. A full characterization of these deuterated extracts is hence pivotal for their use in building up model membrane systems. Here we report the structural characterization of lipid extracts obtained from Pichia pastoris by means of neutron diffraction measurements. In particular, we compare the structure of membranes extracted from yeast cells grown in a standard culture medium and in a corresponding deuterated culture medium. The results show that the different molecular composition of the deuterated and protiated lipid extracts induce different structural organization of the lipid membranes. In addition, we compare these membranes composed of extracted yeast lipids with stacked bilayers prepared from synthetic lipid mixtures.
|
|
| 9. |
- Waldie, Sarah, et al.
(författare)
-
Localization of Cholesterol within Supported Lipid Bilayers Made of a Natural Extract of Tailor-Deuterated Phosphatidylcholine
- 2018
-
Ingår i: Langmuir. - : AMER CHEMICAL SOC. - 0743-7463 .- 1520-5827. ; 34:1, s. 472-479
-
Tidskriftsartikel (refereegranskat)abstract
- Cholesterol is an essential component of mammalian membranes and is known to induce a series of physicochemical changes in the lipid bilayer. Such changes include the formation of liquid-ordered phases with an increased thickness and a configurational order as compared to liquid-disordered phases. For saturated lipid membranes, cholesterol molecules localize close to the lipid head group-tail interface. However, the presence of polyunsaturated lipids was recently shown to promote relocation of cholesterol toward the inner interface between the two bilayer leaflets. Here, neutron reflection is used to study the location of cholesterol (both non-deuterated and per-deuterated versions are used) within supported lipid bilayers composed of a natural mixture of phosphatidylcholine (PC). The lipids were produced in a genetically modified strain of Escherichia coli and grown under specific deuterated conditions to give an overall neutron scattering length density (which depends on the level of deuteration) of the lipids matching that of D2O. The combination of solvent contrast variation method with specific deuteration shows that cholesterol is located closer to the lipid head group-tail interface in this natural PC extract rather than in the center of the core of the bilayer as seen for very thin or polyunsaturated membranes.
|
|
